Structural characterization of two lipophilic tris(tropolonato) gallium(III) and indium(III) complexes of radiopharmaceutical interest

Inorganica

Chimica

Acta,

211 (1993)

141-147

141

Structural characterization of two lipophilic tris(tropolonato) gallium(II1) and indium(II1) complexes of radiopharmaceutical interest F. Nepveu* Laboratoire

and F. Jasanada

de Ciblage

en Thefrapeutique,

Universite’ Paul Sabatier,

35 Chemin

des Maraichers,

F-31062

Toulouse

(France)

L. Walz Mar-Planck-Znstitut (Received

October

fir

Festkiirperforschung,

Heisenbergstrasse

I, D-7000

Stuttgart

80 (Germany)

5, 1992; revised June 18, 1993)

Abstract Tris(tropolonato)gallium(III), GaT,, and tris(tropolonato)indium(III), InT,, have been prepared in water from tropolone and the corresponding metal(II1) nitrate salt and structurally characterized. GaT, (1) crystallizes in the monoclinic space group C2/c with a = 10.899(l), b= 10.282(l), c = 16.970(2) A, p= 103.721(8)” and Z=4. InT, (2) crystallizes in the rhombohedral space group R3c with a = 10.5349(5), b = 10.5349(5), c=32.738(2) 8, and Z=6. The structures have been refined to an R factor of 0.027 for 1,based on 2171 observed reflections, and to an R factor of 0.030 for 2, based on 507 observed reflections. The octahedral coordination of the metal(II1) ions leads to an O-M-O’ bond angle of 81.1(l)” (mean value) in 1 and 75.3(l)” in 2 and to an M-O bond are compared to A1T3 and length of 1.967(l) A ( mean value) in 1 and 2.134(3) 8, in 2. Structural parameters FeT, analogues and show the inflexibility of the tropolonato anion. The structural variations observed in the parameters external to the ring are consistent with the variation of the ionic radius in this series. The five signals ligand. A downfield observed on the 13C NMR spectra are consistent with the C zV symmetry of the tropolonato shift for each carbon atom is observed upon complexation.

Introduction

Gallium and indium have isotopes that are compatible with current nuclear medical technology, and radiopharmaceuticals based on these two metal ions are in routine use for human studies [l, 21. Only oxidation state(II1) is important for gallium and indium under physiological conditions. The combination of necessary properties such as water solubility, neutral charge and lipophilicity, explains why the coordination chemistry of these elements that is relevant to their radiopharmaceutical development has remained a limited field. In recent years a variety of ligands have been investigated as potential agents for expanding the range of applications for gallium and indium radioisotopes. The bidentate chelating ligands 8-hydroxyquinoline (oxine) and 2-hydroxy-2,4,6_cycloheptatrienone (tropolone, HT) are prominent among these, since they can form neutral and lipophilic complexes and may penetrate cell membranes [3-71.

*Author

to whom

correspondence

should

be addressed.

Physico-chemical data have been presented [8-E] for tris(tropolonato)metal(III) complexes, MT, (T = tropolonato anion), but structural data are limited to the tris(tropolonato)aluminium(III), AlT,, [16] and to the tris(tropolonato)manganese(III), MnT,, [17]. A preliminary account of the structure of FeT, has appeared [18]. No structural data have been reported for gallium(II1) and indium(II1) tropolonates. In this report, the tris(tropolonato)metal(III) complexes,

[Ga(WW,),I

(1) and

[InWW,),]

(21, are

synthesized and spectroscopically characterized. The structures of GaT, and InT, are compared to their Group 13 congener AIT,, and to FeT, because of the similarities between these four metal(II1) ions.

Experimental Material and methods

All chemicals were reagent grade and were used as received. Tropolone and metal nitrates were obtained from Aldrich. Chloroform (Prolabo) was dried over molecular

sieves.

Elemental

analyses

were

performed

Elsevier

Sequoia

143 TABLE

1. Crystallographic

data for 1 and 2

TABLE 2. Final atomic coordinates rameters with e.s.d.s in parentheses

Parameter

1

2

Formula Molecular mass Crystal shape Crystal dimensions Crystal system Space group

GGIK506

InG1K506

433.05

478.15

plate-like 0.6x0.6x0.12 monoclinic C2lc 10.899( 1) 10.282( 1) 16.970(2) 103.721(8) 1847.43 4 1.56 880 14.52 5-60 6915 2704 2171 151 0.26-0.35 0.027

plate-like 0.4 x 0.4 x 0.1 rhombohedral

Atom

(mm)

= (A) b (A) c (A) P( V( R ‘) Z &,I, (cm-‘) F(OOO) p (cm-‘) Scan range, 20 No. reflections Unique Observed (F.> No. parameters Max. and min.

(“) measured 3a(F,)) Ap (e Ad3)

~=~(lF~1-1FJ)~lF~1

R,=[(Cw[Fo]-[Fc])*/&v[Fo]2]'R 0.022

Rf3C

10.5349(5) 10.5349(5) 32.738(2) 90 3146.62 6 1.51 1428 10.51 5-50 1489 625 507 55 0.38-0.35 0.030 0.023

with STRUXI [20]. All hydrogen atoms were observed on a difference-Fourier map and their positions were refined with fixed isotropic thermal parameters (piso = 0.05 &). M aximum shift/e.s.d. in final cycle were < 0.06 for 1 and < 0.005 for 2. The extinction corrections used were 7.7~ 10V4 for 1 and 1.8 X low4 for 2. No significant feature appeared in the final differenceFourier maps. Atomic scattering factors were taken from ref. 21. Diagrams were drawn with SHELXTLPlus [22]. Final atomic coordinates and isotropic thermal parameters (U,, = ( 1/3)&Zj uija *ia*jaiaj) are given in Table 2. Selected interatomic distances and angles are listed in Tables 3 and 4. See also ‘Supplementary material’.

Results

and discussion

The compounds 1 and 2 have been prepared in a manner different from that reported previously [lOa]. The Ga and In complexes of tropolone can be prepared from aqueous solution of the metal nitrate salts with a very good yield. The complexes are soluble in chloroform (lo-’ M) and poorly soluble in water (lop4 M). In vitro partition ratios of the gallium and indium tropolonates, correlated with in viva organ distribution in the rat, have been determined previously by Hendershott et al. [5]. These studies showed that these metal complexes are highly lipid soluble.

x

and isotropic for 1 and 2

Y

thermal pa-

z

ues

Complex Gal 01 02 03 Cl c2 c3 c4 c5 C6 c7 Cl’ C2’ C3’ C4’

0.00000 -0.1184(l) - 0.1230( 1) 0.0577( 1) -0.1135(l) - 0.1996(2) - 0.2113(2) -0.1398(2) - 0.0363(2) 0.0209(2) -0.0093(l) - 0.0687( 1) - 0.1459(2) -0.1166(2) 0.00000

0.14936(2) 0.0047(l) 0.2782(l) 0.1642(l) 0.3054(l) 0.3927(2) 0.4347(2) 0.4061(2) 0.3261(2) 0.2545(2) 0.2409(l) -0.1090(l) -0.2188(2) -0.3501(2) - 0.4089(2)

0.75000 0.7164(l) 0.6931(l) 0.6488( 1) 0.6204(l) 0.5734( 1) 0.4940( 1) 0.4398( 1) 0.4524( 1) 0.5204( 1) 0.5954( 1) 0.7322( 1) 0.7169(l) 0.7261(l) 0.75000

0.0327(l) 0.0389(5) 0.0367(5) 0.0403(5) 0.0332(7) 0.0421(8) 0.0498(9) 0.0557(10) 0.0569(11) 0.0493(10) 0.0353(7) 0.0309(7) 0.0374(8) 0.0426(8) 0.0473(13)

Complex In 01 Cl c2 c3 c4

2 0.00000 0.1909(4) 0.2887(6) 0.4160(7) 0.5352(9) 0.5666(9)

0.00000 0.0609(4) 0.0339(5) 0.0710(7) 0.0574(9) 0.0000

0.25000 0.2140( 1) 0.2298(l) 0.2076(2) 0.2162(2) 0.2500

0.0325(4) 0.041(2) 0.036(2) 0.052(3) 0.0743(10) 0.090( 10)

TABLE for 1

3. Bond lengths (A)

1

0(2)-C(l) 0(3)-C(7) C(lW(2) C(2)-c(3) C(3)-c(4) C(4)-c(5) C(5)<(6) C(6)<(7) C(7)-c(l) G(l)-c(l’) C(l’)-C(2’) C(2’)-C(3’) C(3’)-C(4’)

1.963(l) 1.967(l) 1.970(l) 1.288(2) 1.293(2) 1.289(2) 1.402(2) 1.392(3) 1.371(3) 1.371(3) 1.386(3) 1.395(3) 1.463(2) 1.288(2) 1.395(2) 1.388(2) 1.379(2)

O(l)-Ga(l)-O(la) O(l)-Ga(l)-O(2) O(l)-Ga(l)-O(2a) O(l)-Ga( 1)-O(3) O(l)-Ga( l)-O(3a) O(2)-Ga( l)-O(2a) O(2)-Ga(l)-O(3) O(2)-Ga( l)-O(3a) 0(3)-Ga( l)-O(3a)

81.4(l) 92.5( 1) 167.7( 1) 97.5(l) 89.3(l) 95.3(l) 80.8( 1) 93.1(l) 171.1(l)

Ga(l)-O(1) Ga( 1)-O(2) Ga(l)-O(3) 0(1)-C@‘)

and bond

angles (“) with e.s.d.s

C(l)-O(2)-Ga(1) C(7)-O(3)-Ga(

1)

0(2)-c(l)-C(2) G(2)<(1)-C(7) C(2)-C( 1)-C(7) W-c(7)-C(6) 0(3)-c(7)-C(1) C(l)-c(2)-~(3) C(2)-C(3)-C(4) C(3)-C(4)-c(5) C(4)-C(5)-C(6) C(5)-C(6)-C(7) C( l)-C(7)-C(6) C( 1‘)-0( l)-Ga( 1) O( 1)X( l’)-C(2’) O(l)-C(l’)-C(l’a) C(2’)-C(l’)-C(l’a) C(l’)-c(2’)-C(3’) C(4’)-C(3’)-C(2’) C(3’)-C(4’)-C(3’a)

114.5(l) 114.6(l) 119.1(l) 114.9(l) 126.0(2) 119.1(2) 115.1(l) 130.1(2) 130.3(2) 127.0(2) 129.7(2) 131.1(2) 125.8(l) 114.3(l) 119.4(l) 114.9(l) 125.8(l) 130.9(2) 129.2(2) 127.9(2)

144

TABLE for 2

4. Bond

In( l)-0(

1)

lengths

(A)

and

bond

angles

(“) with

e.s.d.s

2.134(3) 1.304(8) 1.464(6) 1.398(8) 1.362(14) 1.378(10)

0(1)-C(l) C(l)-C(1’) C(l)-C(2) C(2)-C(3) C(3)-C(4)

75.3( 1) 92.4( 1) 103.2( 1) 160.4(2) 116.4(3) 119.1(4) 132.1(6) 130.4(7) 125.2(7)

O(l)-In(l)-O(lc) O(l)-In( O(l)-In(l)-O(le) O(l)-In(l)-O(ld) In(l)-0(1)-C(l) O(l)-C(l)-C(2) C(l)-C(2)<(3) C(2)-C(3)-c(4) C(3)-C(4)-C(3’)

each carbon atom, upon complexation, with the strongest effect on [l] (and [l’]). These observed chemical shifts are comparable to those reported for the galliumdimethyltropolonate complex [23]. The typical and intricate ABB’CC’M pattern, which is observed in the ‘H NMR spectrum of HT, at room temperature and in CDCl,, persists for 1 and 2 in the form of a BB’CC’M system (Fig. 2). The pattern is composed of two distinct multiplets. The first one is a triplet (H4) centred at 7.03 ppm for HT, and at 7.11 and 7.10 ppm for 1 and 2, respectively. The second multiplet is centred at 7.35 ppm for HT (Hl, H2, H2’, H3, H3’), and at 7.59 and 7.55 ppm for 1 and 2, respectively (H2, H2’, H3, H3’). These results show a slight downfield shift for each multiplet upon complexation.

H2.H3.H6

and HB

I

_

,---

H4

----k-u

L1 1

H2kl3.M

pm

and Ii6

AhI -! A_

Fig.

ix0

Ihi,

,111

1. 13C NMR

,211

spectra

,,,,I

x0

in CDCI,

60

ill

for

1 and

3,

ppmiMS

7.0

S

/

h.

7.1

21X1

---Lrt.

L_-

7.5

mm

H4

L_

--uhJ-

,.O

2. HZ.H3.M

The IR spectral pattern (1613-713 cm-‘), which is characteristic of tropolone [15], is preserved in the complexes, with a general bathochromic shift upon complexation (see ‘Experimental’). The observed bands are in agreement with IR spectral studies reported [ll] also recently [15] for GaT,. The 13C NMR spectra of 1 and 2 exhibit five signals due to the C,, symmetry of the seven carbon atom ring (Fig. 1). Chemical shifts for 1,2 and HT are given in ‘Experimental’. A downfield shift is observed for

and H8

pm Fig. 2. ‘H NMR

spectra

in CDC13 for 1 and 2 and for tropolone.

14.5

The crystal structures of Ga(T,) (1) and In(T,) (2) have been solved. 1 and 2 are not isomorphous. The gallium complex is isomorphous with tris(tropolonato)aluminium(III) (3) [16], and the indium(II1) complex appears to be isomorphous with the iron(II1) analogue, 4 [18]. Drawings of single molecules of 1 and 2 are given, along with appropriate atom numbering schemes, in Figs. 3 and 4, respectively. A more complete picture of InT, is accessible by examination of the stereoview (Fig. 5). There is no relationship between the two structures in the sense of super-group --j sub-group. The crystal structure of 1 consists of neutral Ga(T,) units. The twofold symmetry causes the asymmetric unit to contain one-half of a metal ion, and one and a half of the ligand. The octahedral coordination of gallium by oxygens from three tropolonate anions is approximately octahedral, but deviates from the ideal configuration. The compression is seen on the O(l)-Ga-O(la) and O(2)-Ga-O(3) angles involving oxygen atoms from the same ligand, which are 81.4 c4

Fig. 3. Perspective

view of the Ga(T,)

Fig. 4. Perspective

view of the In(T,)

molecule

molecule

(1).

(2).

(1) and 80.8 (l)“, respectively. This can be a consequence of the dimensions of the rigid seven-ring tropolonate ligand. The exocyclic O(l)-Ga-O(3) (97.5 (1)“) and O(2)-Ga-O(2a) (95.3 (1)“) angles are both greater than 90”, as are the exocyclic O(l)-Ga-O(2) (92.5 (1)“) and O(2)-Ga-O(3a) (93.1 (1)“) angles. This two-fold axis forces equality of the two Ga-0( 1) distances, but allows dissimilarity of Ga-O(2) and Ga-O(3) distances. The average Ga-0 distance is 1.967 A, while individual values are in the range 1963(1)-1.970(l) 8, and are not significantly different. This mean distance is within the range of values found in comparable gallium complexes with 3-hydroxy-4-pyridinonate or hydroxamate as ligands [24, 251. There is no significant difference between O(2)-C( 1) and 0(3)-C(7) bond lengths, showing the strong delocalization of the ligand (from initial distinct keto and hydroxy functions) upon complexation. The ligand is planar within experimental error (see ‘Supplementary material’), Ga being displaced 0.13 8, maximum from this plane. Complex 2 presents a comparable molecular structure but with a higher symmetry. The indium atom is on the 32 position and this forces 32 symmetry on the complex as a whole. The asymmetric unit consists of one-sixth of a metal ion and one-half of the ligand. The result is that there is only one independent In-O(l) bond length (2.134(3) A), which is within the range of values found in comparable indium complexes [24, 251. The 0(1)-C(l) bond length of 1.304(8) 8, is slightly longer than in 1. There is a stronger compression of the In(T,) units from 0, down the three-fold axis, leading to an intraring O(l)-In-O(lc) angle of 75.3(l)” compared with the average value of 81.1(l)’ for the Ga analogue. The exocyclic O(l)-In-O(l) angles are also smaller than in the Ga analogue. This 32 symmetry imposed by the special crystallographic position at the metal ion (32) leads to a 50/50 mixture of A and A molecules in the crystal. Some geometric parameters of the four tris(tropolonato)metal(III) complexes, AIT,, GaT,, InT, and FeT, are compared in Table 5. The M-O bond length increases, and the O-M-O’ angle decreases as the ionic radius of the metal(II1) ion increases. For FeT,, the 0.. .O’ distance value is intermediate between those of AlT, and GaT, and the Cl-Cl’ bond length is not significantly different from those of GaT, and InT-,. In 1 the dihedral angle between O(1) O(2) O(3a) and O(la) O(2a) O(3) is 2.4” and the twist angles (&a, &, &J are not equivalent with an average value of 46.7”. This average twist angle value is comparable to that observed in AlT, having the same crystallographic symmetry and lower than the 60” value for an idealized trigonal antiprism as in 2 or in FeT,. There is no averaging of the C-C bonds in the tropolonato ligand, which are similar to those observed in tropolone, HT

146

Fig.

5. Stereoview

TABLE

Compound

along

5. Comparison

Ionic radiusb

c of the

of geometric

O-M-O’

unit

cell of In(TS)

parametersa

O...O’

(2).

in tristropolonatometal(II1)

M-G

HT

complexes

O-Cl

Cl-cl’

Cl-C2

C2-C3

c3-c4

Reference

1.261(3) 1.333(3)

1.454(4)

1.410(4) 1.379(4)

1.373(4) 1.393(4)

1.410(3) 1.341(4)

27

AITXd

0.68

82.6(4)

2.490(6)

1.888(Z)

1.291(l)

1.450(l)

1.397(l)

1.384(2)

1.371(5)

16

GaT,

0.76

81.1(l)“

2.558(2)

1.967”(l)

1.290d(2)

1.463(2)

1.395(3) 1.402(2)

1.386(3) 1.392(3)

1.371(3) 1.371(3)

this work

InT,

0.94

75.3(l)

2.607(4)

2.134(3)

1.304(8)

1.464(6)

1.398(8)

1.362(14)

1.378(10)

this work

FeT,

0.79

77.8(l)

2.522(4)

2.008(3)

1.294(5)

1.463(7)

1.397(2)

1.385(7)

1.379(7)

18

“Angles

(“) and

distances

(A) with

estimated

errors.

‘Ref.

26, coordination

[27] (1.454-1.375 A). The C(l)-C(1’) length of 1.462 8, is significantly greater than other bonds in the ring, not included in the r-electron delocalization. The Cl-C2 distance is the longest of the three other types of C-C distances. A continuous decrease in bond length (Cl-C2> C2-C3 > C3-C4) is observed, except in InT,, but for these lengths e.s.d. values are large. Examination of all distances in these four complexes shows that the variations in the tropolonato ligand distances are very small. Geometric variations are larger in the structural parameters external to the ring. These studies show that, for the same chelating ligand, the tropolonato anion, structural parameters of the iron(II1) analogue are close either to the gallium(III) analogue or to the indium(II1) analogue. These examples illustrate the similarities between the coordination chemistry of the Ga3’, In3+ and Fe3+ metal ions. These similarities are manifested in viva by the binding of all three ions to the serum protein transferrin normally used for ion transport.

Supplementary

material

Lists of systematic extinctions, hydrogen atom parameters, anisotropic thermal parameters, observed and

number

6.

Tropolone.

dMean

values.

calculated structure factors for 1 and 2, least-squares planes and dihedral angles and twist angles for 1, and a stereoview of 1 are available from author F.N. on request.

Acknowledgements

We are grateful to E.M. Peters for plotting the figures and to the French Ministry of National Education for financial support.

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